Compared with its competitors, Diacomit (stiripentol) remains in the top position as an add-on therapy to control epileptic seizures in young children with Dravet syndrome, or in those who are affected by repeated and prolonged seizures, according to an expert review study.
The study, “Stiripentol for the treatment of seizures associated with Dravet syndrome,” was published in Expert Review of Neurotherapeutics.
Dravet syndrome is a severe type of epilepsy that usually manifests during the first year of life and is characterized by seizures, cognitive deficits, and increased mortality.
“First-line drugs usually include valproate (Depacon) and clobazam (Onfi), but seizure response is most often insufficient. STP (stiripentol) proved to be beneficial as an adjunctive therapy in these refractory patients and was approved as an orphan drug in Europe in 2007, followed by Japan and Canada in 2012,” Catherine Chiron, a pediatric neurologist at the Hôpital Necker-Enfants Malades in Paris, France, wrote in the review.
Stiripentol, to be used alongside Onfi, was approved in August 2018 in the U.S., closely following the approval of cannabidiol (Epidiolex) by the FDA for the same indication in June 2018. Another compound, fenfluramine (Fintepla, also known as ZX008), is in the final stage of clinical development in the U.S. and the EU for Dravet syndrome as an adjunctive therapy, she said.
The first indication that Diacomit might be an effective add-on therapy to control seizures came from a large, prospective, open-label basket study in France launched in the early 1990s. The study enrolled a total of 212 children with different types of epilepsy who were treated with Diacomit in combination with standard anti-seizure medications (Depacon and Onfi) .
Results showed that half of the children with Dravet participating in the study experienced a reduction of more than 50% in seizure frequency, and 15% became seizure-free after three months of treatment with Diacomit.
These findings opened the door to the launch of two multicenter, randomized, placebo-controlled Phase 3 clinical trials in France and Italy, which were specifically designed to test the safety and efficacy of Diacomit in children with Dravet as an adjunctive therapy to Depacon and Onfi.
Results from both studies showed that children treated with Diacomit experienced a significant reduction in the frequency of seizures compared with children treated with a placebo, confirming its therapeutic potential as an anti-seizure add-on therapy.
Subsequent long-term observational studies carried out worldwide continued to show Diacomit’s sustained efficacy, and satisfactory safety and tolerability with an exposure period of up to 20 years.
“STP demonstrated indisputable efficacy as adjunctive therapy to (clobazam) and (valproate) through two pivotal trials performed in children 20 years ago, an efficacy continuously confirmed since then all over the world,” Chiron said.
Despite the large amount of promising data generated by clinical trials over the years, in some countries it took more than two decades for Diacomit to be approved. This was in large part caused by concerns raised about the possibility that the anti-seizure effects reported in the studies might not be due to the use of Diacomit per se.
However, recent pharmacokinetic studies have shown the mechanism of action and the anti-seizure effects mediated by Diacomit are independent from those brought about by Onfi. In addition, data from observational studies suggested the therapeutic effects of Diacomit were beneficial to control seizures, even when administered as a stand-alone therapy.
Comparisons with other anti-seizure competitors showed that responder rates seem comparable for Diacomit (71%) and fenfluramine (70%), but lower for cannabidiol (43%), Chiron wrote.
“In the absence of comparative studies between the three compounds, the complementary rather than competitive use of each drug will probably develop thanks to the increasing number of prescriptions: one could speculate that STP may be especially useful before the age of 2 years and in patients with frequent status epilepticus, while cannabidiol would avoid using benzodiazepines … and fenfluramine will keep a significant proportion of patients seizure free,” she said.
With the development of anti-epileptic compounds still being tested in preclinical or preliminary clinical studies, it is likely that the next five years will bring significant advancements to Dravet syndrome treatment, she added.